In the brain region where blood flow is interrupted, cytotoxic brain edema occurs first, followed by vasogenic brain edema. Vasogenic brain edema developes several hours after the occurrence of cerebral ischemia and its progress continues for one week from the onset. Thereafter, brain edema decreases gradually and, depending on the focal range of infarction, the edema persists as an infarcted area for one to three months. Since the brain is covered with the rigid skull, cerebral edema causes an increase in the brain volume. If the cerebral edema exceeds a certain limit, there occurs an abrupt increase in the tissue pressure and the intracranical pressure, often inducing fatal hernia and eventually aggravating the encephalopathy to determine the scope of the subsequent infarcted area (Siesjo, J. Neurosurg. 77, 169-184, 1992). Thus, the treatment of cerebral edema which is critical to the patient's life and the prognosis of his disease is clinically a very important objective. The three primary methods currently used to treat cerebral edema are hyperpnea, the drainage of cerebrospinal fluid and the use of hypertonic solutions, steroids or the like; however, in almost all cases, these methods provide only temporary ameliorative effects and there is not much promise for the therapeutic efficacy to be finally achieved (Siesjo, J. Neurosurg. 77, 337-354, 1992). Therefore, it has been desirable to develop drugs that have an entirely different mechanism of action and which will prove effective in the treatment of ischemic cerebrovascular disorders.
The present inventors previously found that N.sup.G -nitro-L-arginine (L-NNA), a NOS inhibitor, was capable of ameliorating cerebral edema and infarction that were developed after focal cerebral ischemia (Nagafuji et al., Neurosci. Lett., 147, 159-162, 1992), as well as the neuronal cell death that was also developed after transient global cerebral ischemia (Nagafuji et al., Eur. J. Pharmacol. Env. Tox., 248, 325-328, 1993). However, it has also been reported that relatively high doses of NOS inhibitors are not only ineffective against ischemic brain damage but also they sometimes aggravate it (Iadecola et al., J. Cereb. Blood Flow Metab., 14, 175-192, 1994).
A presently dominant theory based on genetic DNA analyses holds that NOS exists in at least three isoforms, namely, N-cNOS which is mainly present constitutively in neurons, E-cNOS which is mainly present constitutively in vascular endothelial cells, and iNOS which is induced from transcriptional level on stimulation by cytokines and/or endotoxins in macrophages and other cells. Among these three isoforms, N-cNOS and E-cNOS are calcium-dependent whereas iNOS is not calcium-dependent (Nathan et al., FASEB J., 16, 3051-3064, 1992).
A mechanism that has been proposed as being most probable for explaining disorders in the brain tissue which accompany cerebral ischemia is a pathway comprising the sequence of elevation in the extracellular glutamic acid level, hyperactivation of glutamic acid receptors on the post-synapses, elevation in the intracellular calcium level and abnormal activation of calcium-dependent enzymes (Siesjo, J. Cereb. Blood Flow Metab. 1, 155-185, 1981; Siesjo, J. Neurosurg. 60, 883-908, 1984; Choi, Trends Neurosci. 11, 465-469, 1988; Siesjo and Bengstsson, J. Cereb. Blood Flow Metab. 9, 127-140, 1989). As already mentioned, N-cNOS is calcium-dependent, so the inhibition of abnormal activation of this type of NOS isoform would contribute to the neuroprotective effects of NOS inhibitors (Dawson et al., Annals Neurol. 32, 297-311, 1992).
It is also known that NO is at least one of the essences of endothelium-derived relaxing factor (EDRF), so if E-cNOS is inhibited by a more-than-necessary degree, the cerebral vasculare will be constricted and the blood flow will decrease whereas the blood pressure will increase, thereby aggravating the dynamics of micro-circulation, possibly leading to an expansion of the ischemic lesion.
Therefore, if a therapeutic for ischemic cerebral diseases is to be developed, a NOS inhibitor is desirable that inhibits E-cNOS only weakly but which strongly inhibits N-cNOS (Nowicki et al., Eur. J. Pharmacol., 204, 339-340, 1991; Dawson et al., Proc. Natl. Acad. Sci. USA, 88, 6368-6371, 1991). No reports have yet been published showing that certain of the NOS inhibitors highly selectively for N-cNOS in comparison with the E-cNOS inhibiting action in the manner just described above.
Upon stimulation by certain kinds of cytokines and/or endotoxins, iNOS is induced in immunocytes such as macrophages and glial cells and other cells, and the resulting large amount of NO will cause a fatal drop in blood pressure. Therefore, it is speculated that an iNOS selective inhibitor may be effective against hypotension and other symptoms of sepsis (Kilbourn and Griffith, J. Natl. Cancer Inst. 84, 827-831, 1992; Cobb et al., Crit. Care Med. 21, 1261-1263, 1993; Lorente et al., Crit. Care Med. 21, 1287-1295, 1993).
Aminoguanidine (AG) is the only compound that has ever been reported to show selectivity for iNOS in comparison with the E-cNOS inhibiting action (Griffith et al., Br. J. Pharmacol. 110, 963-968, 1993); however, the inhibiting potency and selectivity for iNOS of this compound is insufficient to warrant its use as a therapeutic effective against hypotension in sepsis.